32.5SS Associated with Other Systemic Autoimmune Diseases

32.5.1Mixed Connective Tissue Disease

Mixed connective tissue disease (MCTD) is a controversial entity [53]. The original description was of a relatively mild disorder with overlapping features of SLE, polymyositis and SSc in association with antibodies to nRNP. However, it has become clear that antibodies to nRNP are relatively common in SLE, and many patients presenting with the above features tend to differentiate over time into a phenotype where the features of one of the three diseases predominates over the other two. Therefore, the evaluation of any association with SS is difficult, particularly as clinical features such as Raynaud’s and non-erosive arthritis are common to both conditions.

Ohtsuka et al. reported that ‘secondary SS’ and sialectasia are more common in MCTD than in any other autoimmune disease [54]. Raynaud’s phenomenon, arthritis, myositis, sclerodactyly, fever, cutaneous erythema, and lymphadenopathy occurred more frequently in MCTD than in pSS. The frequency of these manifestations was no different in MCTD with sSS than in MCTD alone. The ESR and CRP level were higher in MCTD than pSS. Antinuclear antibodies, anti-dsDNA antibodies and anti-RNP antibodies were more prevalent in the former. However, there were no differences in inflammatory markers or autoantibody profile between MCTD without and without sSS. There was a strict dissociation between the presence of anti-RNP antibodies and anti-La antibodies in both MCTD and pSS patients.

A longitudinal study of 55 patients with MCTD, all of whom had antibodies to RNP, found that sicca symptoms (defined as daily oral dryness, frequent use of liquid because of oral dryness, or daily ocular dryness) occurred in 41.8% of patients [55]. The length of the follow period ranged from 3 to 30 years (mean 9 years). Common clinical characteristics of the patients included Raynaud’s phenomenon, swollen hands, gastro-esophageal reflux, arthralgia, myalgia, serositis, lymphopenia and reduced gas transfer on pulmonary function testing. Patients were not assessed with more quantitative methods such as Schirmer’s test, salivary gland biopsy, unstimulated salivary flow or sialography, so how many met the AECG criteria for sSS is unknown. 32.7% of patients had antibodies to Ro, but only 2 patients (3.6%) had antibodies to La. Anti-Ro antibodies were strongly associated with malar rash and photosensitivity, in keeping with previous observations. There was no association between sicca symptoms and anti-Ro antibodies.

The authors stated, rather surprisingly, that no patients evolved into a diagnosis of SLE or SSc over the follow-up period. However, many of the clinical features of the patients described occur in both SLE and primary SS. Given that the patients were not fully assessed for SS, one can speculate that at least some of their patients would fit the criteria for pSS. Furthermore, MCTD is an overlap syndrome; it is therefore debatable whether patients with MCTD and features of the SS should be considered to have sSS. Rather, the presence of sicca symptoms could be considered a manifestation of the overlap syndrome, and not the development of a second autoimmune disease.

32 Sjögren’s Syndrome and Associations with Other Autoimmune and Rheumatic Diseases 469

32.5.2Systemic Vasculitis

Vasculitis occurring in pSS is typically considered as a manifestation of the primary disease and is strongly associated with cryoglobulinemia. This is detailed in Chap. 12. True co-existence of a well-defined primary systemic vasculitis with pSS is very rare, and limited to a handful of cases [56, 57]. Positive ANCA immunofluorescence tests are often found in pSS [16], but do not by themselves indicate the presence of an ANCA-associated vasculitis.

32.5.3Antiphospholipid Syndrome (APS)

Antiphospholipid antibodies are detectable in 13% of pSS patients, but only 1% have the antiphospholipid syndrome itself [51]. A small number of pSS patients with antiphospholipid antibodies not meeting the criteria for APS nevertheless have certain APS-like features including thrombocytopenia, livedo reticularis and hemolytic anemia.

32.5.4Sarcoidosis

Sarcoidosis is a systemic autoimmune process characterized pathologically by the presence of non-caseating granulomata. It can present with parotid swelling and sicca symptoms, making it difficult to distinguish from pSS clinically. A firm diagnosis depends on demonstrating the characteristic histological findings on biopsy, and may be difficult to achieve. Drosos et al. reported five cases of sarcoidosis presenting with sicca symptoms [58]. All five patients had abnormal Rose-Bengal staining, four had an abnormal Schirmer’s test, and three had reduced parotid flow rate. Minor salivary gland biopsy revealed scattered lymphoplasmacytic infiltrates in all patients, with concurrent non-caseating granulomata in three. In the remaining two patients, the diagnosis of sarcoidosis was made by demonstrating non-caseating granulomata on transbronchial lung biopsy.

The currently accepted AECG criteria for pSS has sarcoidosis as an exclusion criterion. Therefore, by this definition, the two disorders cannot co-exist. However, Ramos-Casals and colleagues [59] have reported five cases of sarcoidosis with coexistent pSS (as defined by the previously used and less restrictive European Consensus Criteria). All five patients had the typical focal lymphocytic sialadenitis of pSS and biopsy–proven sarcoidosis. None of the five patients had antibodies to Ro and La, which is rather surprising if they had true pSS. Perhaps rather than there being two coexistent autoimmune diseases, the sialadenitis in these patients was a manifestation of the sarcoidosis. Certainly, early pulmonary sarcoidosis can present histopathologically as alveolitis with lymphocytic foci prior to the development of granulomata. It is not unreasonable to assume that an analogous sequence of events

could occur in the salivary glands. A further 28 cases from the literature have been identified in which the histology suggested co-existence of pSS and sarcoidosis [59]. The patients said to have both pSS and sarcoidosis had more frequent articular symptoms, uveitis, and positive RF, ANA and anti-Ro antibodies, than patients with a single diagnosis of sarcoidosis mimicking pSS.

Drosos’ case series detailed above demonstrated that lymphoplasmacytic salivary gland infiltrates do occur in sarcoidosis. However, the same group have shown that, at least when interpreted by expert histopathologists, salivary gland biopsy is a reliable discriminator between pSS and sarcoidosis [60]. Sixty labial minor salivary gland biopsies (from 32 patients with definite sarcoidosis and 28 with pSS) were retrospectively reviewed by a histopathologist unaware of the diagnosis or clinical details. Non-caseating granulomata were identified on six biopsies, all of which were from sarcoidosis patients. Twelve biopsies, again all from sarcoidosis patients, showed scattered lymphocytic infiltrates with a Tarpley’s score of £1+. The remainder of the sarcoidosis patients had normal biopsies. All 28 pSS patients had a Tarpley’s score of ³2+. Thus, although lip biopsy has a low sensitivity for diagnosing sarcoidosis, it can reliably distinguish it from pSS.

32.6 SS Associated with Organ-Specific Autoimmune Diseases

32.6.1SS Associated with Autoimmune Thyroiditis

The literature in this area is confused. There is debate as to whether the development of SS symptoms in patients with autoimmune thyroiditis is a form of secondary SS, an overlap syndrome, or the co-existence of two separate autoimmune diseases. When autoimmune thyroiditis develops in a patient with pSS there is again dispute as to whether this represents two separate diagnoses, or a manifestation of the primary SS.

There is a strong association between pSS and thyroid disease, particularly autoimmune hypothyroidism [61]. Subclinical hypothyroidism is the most common endocrine abnormality. A study of 33 pSS patients found autoimmune thyroiditis in 24% and autoimmune hyperthyroidism in 6% [62]. Autoantibodies against thyroid peroxidase and thyroglobulin were detected in 45% and 15% respectively. A British prospective longitudinal study of 100 pSS patients found that 14% also had thyroid disease [63]. Another UK study involving a retrospective case review of 114 patients with pSS found that hypothyroidism occurred in a similar proportion [2]. In the latter study, hypothyroidism was diagnosed prior to the pSS in 12 cases, concurrently in 1 case, and a year or more after the time of pSS diagnosis in 3 patients. Only 2 patients (1.8%) had Grave’s disease. A French study prospectively followed 137 patients with pSS, all female, for a mean duration of 6 years [64]. They found 22% of cases had thyroid dysfunction

32 Sjögren’s Syndrome and Associations with Other Autoimmune and Rheumatic Diseases 471

at diagnosis, compared to only 6% in a control group. The commonest thyroid disease was Hashimoto’s thyroiditis. The presence of rheumatoid factor and anti-Ro antibodies were associated with increased risk of thyroid disease. Of the pSS patients with normal thyroid function at initial diagnosis, 12 developed thyroid disease during the follow up period; most frequently Hashimoto’s thyroiditis. Most of these patients had antibodies to thyroid peroxidase and/ or thyroglobulin at initial evaluation. Ramos-Casels et al. found that 20% of pSS patients had autoimmune thyroid disease, but this was no higher than in their controls [65]. They confirmed the association between thyroid disease and antibodies to thyroid peroxidase and thyroglobulin, as well as anti-parietal cell antibodies.

Eighteen percent of 28 pSS patients had autoimmune thyroiditis, and 35% had thyroglobulin and/or antimicrosomal autoantibodies [66]. Ten percent of 400 Hungarian pSS patients had autoimmune thyroid disease: 7% Hashimoto’s thyroiditis and 3% Graves’ disease [67]. In contrast, a study of 53 Turkish patients did not find an association between pSS and autoimmune thyroid disease or thyroid autoantibodies [68].

The converse relationship between the two diseases also holds true, with pSS occurring ten times more frequently in patients with autoimmune thyroid disease than in the general population. Of 63 prospectively evaluated patients with autoimmune thyroiditis, 4 had autoimmune sialadenitis and 6 had objective keratoconjunctivitis sicca and xerostomia [66]. Only one patient had antiRo antibodies and none had anti-La antibodies. This association may reflect common pathogenic mechanisms. There are shared immunogenetic influences in autoimmune hypothyroidism and pSS, with both diseases associated with HLA-DR3 [69], and similarities between the target organ antigens. Anti- a-fodrin antibodies occur in Hashimoto’s thyroiditis. A study of 61 patients with pSS, 27 with Hashimoto’s thyroiditis alone, and 31 patients with SS associated with thyroiditis found no difference in the prevalence of these antibodies between the groups [70].

Thus, thyroid autoantibodies should be checked at the time the diagnosis of pSS is made and regular measurement of thyroid function at follow-up clinic visits is advised. Conversely, patients with autoimmune hypothyroidism should be evaluated for clinical and immunological evidence of SS.

32.6.2SS Associated with Autoimmune Liver Disease

The association between liver disease and SS was first identified in 1954 [71], and is discussed in detail in Chap. 17. Debate exists as to whether SS occurring in the context of autoimmune liver disease (particularly primary biliary cirrhosis) is ‘secondary’ in the way that sSS occurs in RA, or whether it reflects co-existence of two autoimmune conditions (pSS and autoimmune liver disease).